Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease
Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neu...
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creator | Tagliabracci, Vincent S. Girard, Jean Marie Segvich, Dyann Meyer, Catalina Turnbull, Julie Zhao, Xiaochu Minassian, Berge A. DePaoli-Roach, Anna A. Roach, Peter J. |
description | Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a–/– mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen. |
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A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a–/– mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M807428200</identifier><identifier>PMID: 18852261</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Disease Models, Animal ; Dual-Specificity Phosphatases - genetics ; Dual-Specificity Phosphatases - physiology ; Ethanol - chemistry ; Glycogen - chemistry ; Humans ; Lafora Disease - genetics ; Lafora Disease - metabolism ; Metabolism and Bioenergetics ; Mice ; Mice, Transgenic ; Models, Biological ; Models, Genetic ; Phosphates - chemistry ; Polymers - chemistry ; Protein Tyrosine Phosphatases, Non-Receptor - genetics ; Protein Tyrosine Phosphatases, Non-Receptor - metabolism ; Time Factors</subject><ispartof>The Journal of biological chemistry, 2008-12, Vol.283 (49), p.33816-33825</ispartof><rights>2008 © 2008 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>Copyright © 2008, The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c601t-bca3056b5eeddd9d5057b27278f27e78d3fbe0f039ea43310cfee041338c8ccf3</citedby><cites>FETCH-LOGICAL-c601t-bca3056b5eeddd9d5057b27278f27e78d3fbe0f039ea43310cfee041338c8ccf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2590708/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2590708/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18852261$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tagliabracci, Vincent S.</creatorcontrib><creatorcontrib>Girard, Jean Marie</creatorcontrib><creatorcontrib>Segvich, Dyann</creatorcontrib><creatorcontrib>Meyer, Catalina</creatorcontrib><creatorcontrib>Turnbull, Julie</creatorcontrib><creatorcontrib>Zhao, Xiaochu</creatorcontrib><creatorcontrib>Minassian, Berge A.</creatorcontrib><creatorcontrib>DePaoli-Roach, Anna A.</creatorcontrib><creatorcontrib>Roach, Peter J.</creatorcontrib><title>Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Lafora disease is a progressive myoclonus epilepsy with onset in the teenage years followed by neurodegeneration and death within 10 years. A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a–/– mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen.</description><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Dual-Specificity Phosphatases - genetics</subject><subject>Dual-Specificity Phosphatases - physiology</subject><subject>Ethanol - chemistry</subject><subject>Glycogen - chemistry</subject><subject>Humans</subject><subject>Lafora Disease - genetics</subject><subject>Lafora Disease - metabolism</subject><subject>Metabolism and Bioenergetics</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Models, Biological</subject><subject>Models, Genetic</subject><subject>Phosphates - chemistry</subject><subject>Polymers - chemistry</subject><subject>Protein Tyrosine Phosphatases, Non-Receptor - genetics</subject><subject>Protein Tyrosine Phosphatases, Non-Receptor - metabolism</subject><subject>Time Factors</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE1v1DAQhi1ERbcLV47gA-oty9jOh3NBqpayVNoKJKjEzXKc8cZVEm_tbKv-e1xlReGAD2NL8_j1-CHkLYMVgyr_eNuY1bVMJy45wAuyYCBFJgr26yVZAHCW1byQp-QsxltIK6_ZK3LKpCw4L9mCbC6a0YdB9_QaJ9343sWBeks3_aPxOxzp987HfacnpDpSTdf6EJFaH-hWp6rpZxdRR3xNTqzuI7457kty8-Xy5_prtv22uVpfbDNTApuyxmgBRdkUiG3b1m0BRdXwilfS8gor2QrbIFgQNepcCAbGIkLOhJBGGmPFknyac_eHZsDW4DgF3at9cIMOj8prp_7tjK5TO3-veFFDldwsyfkxIPi7A8ZJDS4a7Hs9oj9EVdYyr4DVCVzNoAk-xoD2zyMM1JN7ldyrZ_fpwru_R3vGj7IT8GEGOrfrHlxA1ThvOhwUl0LltUq_ZGXC3s-Y1V7pXXBR3fzgwASwosxL-RQkZwKT6XuHQUXjcDTYplAzqda7_w35Gzx7qGo</recordid><startdate>20081205</startdate><enddate>20081205</enddate><creator>Tagliabracci, Vincent S.</creator><creator>Girard, Jean Marie</creator><creator>Segvich, Dyann</creator><creator>Meyer, Catalina</creator><creator>Turnbull, Julie</creator><creator>Zhao, Xiaochu</creator><creator>Minassian, Berge A.</creator><creator>DePaoli-Roach, Anna A.</creator><creator>Roach, Peter J.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20081205</creationdate><title>Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease</title><author>Tagliabracci, Vincent S. ; 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A characteristic is the widespread formation of poorly branched, insoluble glycogen-like polymers (polyglucosan) known as Lafora bodies, which accumulate in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual specificity protein phosphatase family that is able to release the small amount of covalent phosphate normally present in glycogen. In studies of Epm2a–/– mice that lack laforin, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. At three months, glycogen metabolism remained essentially normal, even though the phosphorylation of glycogen has increased 4-fold and causes altered physical properties of the polysaccharide. By 9 months, the glycogen has overaccumulated by 3-fold, has become somewhat more phosphorylated, but, more notably, is now poorly branched, is insoluble in water, and has acquired an abnormal morphology visible by electron microscopy. These glycogen molecules have a tendency to aggregate and can be recovered in the pellet after low speed centrifugation of tissue extracts. The aggregation requires the phosphorylation of glycogen. The aggregrated glycogen sequesters glycogen synthase but not other glycogen metabolizing enzymes. We propose that laforin functions to suppress excessive glycogen phosphorylation and is an essential component of the metabolism of normally structured glycogen.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18852261</pmid><doi>10.1074/jbc.M807428200</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Disease Models, Animal Dual-Specificity Phosphatases - genetics Dual-Specificity Phosphatases - physiology Ethanol - chemistry Glycogen - chemistry Humans Lafora Disease - genetics Lafora Disease - metabolism Metabolism and Bioenergetics Mice Mice, Transgenic Models, Biological Models, Genetic Phosphates - chemistry Polymers - chemistry Protein Tyrosine Phosphatases, Non-Receptor - genetics Protein Tyrosine Phosphatases, Non-Receptor - metabolism Time Factors |
title | Abnormal Metabolism of Glycogen Phosphate as a Cause for Lafora Disease |
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